Systems comprising a composite backing and methods for long term transdermal administration

ABSTRACT

Devices, systems, compositions and methods for long term or prolonged transdermal administration of an active agent are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/273,288, filed Dec. 30, 2015; this application also claims thebenefit of U.S. Provisional Application No. 62/367,055, filed Jul. 26,2016, both of which are incorporated herein by reference in theirentirety.

TECHNICAL FIELD

The subject matter described herein relates to a transdermal deliverysystem comprising a backing for improved long term administration. Thedelivery system is suitable for prolonged administration of an active ortherapeutic agent with improved adhesion to the skin at anadministration site.

BACKGROUND

Transdermal delivery systems have become more desirable as they have theadvantage of avoiding difficulties associated with gastrointestinalabsorption of an active agent (e.g. effect of gastrointestinal pH and/orenzyme activity on the active agent, drug-food interactions,gastrointestinal side effects, eliminates pulsed entry into systemcirculation, and avoids high first-pass effect through the liver).Transdermal delivery systems may also increase patient compliance due tothe ability for the patient to self-administer and avoids more invasivetreatments such as injections. Transdermal delivery may advantageouslyprovide controlled, constant delivery of the active agent, which mayresult in less fluctuation in circulating levels of the agent ascompared to oral delivery.

Long term administration of transdermal patches is challenging,especially for patches that use occlusive backings. Most transdermalpatches cannot remain adhered to the skin or other administration sitefor an extended period of time, e.g. at least or about 7 days. However,continuous contact of the patch with the patient's skin is necessary forproper drug delivery from the patch. The FDA lists problems associatedwith transdermal patches include the patch not flexing or conforming tothe skin; the patch not sticking or the edges of the patch curling after24 hours (www.fda.gov). Disadhesion may alter or prevent delivery of thedrug from the patch. Friction between the layers of the patch and theadministration site may cause the patch to buckle, wrinkle, and/or failby losing contact with the skin. To address these problems, transdermalpatches that are approved for long term use are of small size (e.g. lessthan 25 cm²) such as the Catapres® or Ortho Evra® patches or require anover-sized overlay to cover the patch. The use of an overlay increasespatch size and results in about a 2-3 fold increase in the total patcharea. Therefore, use of an overlay is only practical for relativelysmall patches (e.g. not more than about 40 cm²). Many of the multi-dayuse patch manufacturers recommend using medical tape to secure thepatch. For example, the patient instructions for the fentanyl Duragesic®patch recommends applying first aid tape at the edges or use of adhesivedressings as a patch overlay to prevent the problem of patches that donot stick to the skin properly (see www.duragesic.com).

Another approach to long term transdermal patches is the use of arelatively breathable backing layer to increase wear time. Success withthese patches is limited as the increased breathability of the backinglayer reduces drug flux requiring an increase in total patch area.

Therefore, there exists a need for transdermal compositions, devices andmethods that address at least these shortcomings.

The foregoing examples of the related art and limitations relatedtherewith are intended to be illustrative and not exclusive. Otherlimitations of the related art will become apparent to those of skill inthe art upon a reading of the specification and a study of the drawings.

BRIEF SUMMARY

The following aspects and embodiments thereof described and illustratedbelow are meant to be exemplary and illustrative, not limiting in scope.

It is an object of the present invention to provide methods andcompositions to effect long term or prolonged transdermal delivery of anactive agent.

In a first aspect, a composite backing layer for use in a transdermalpatch is provided. In embodiments, the composite backing layer comprisesa first layer comprised of a polymer fabric or a polymer film having astretchability of at least about 5% in at least one direction; a secondlayer comprised of one or more adhesive polymers; and a third layercomprised of one or more polymers. Typically, the first and secondlayers are in contact and the second and third layers are in contact.

In some embodiments, the polymer fabric or polymer film is comprised ofone or more polymers selected from polyesters, polyethylenes,polypropylenes, polyvinylchloride, polyethylene vinyl acetate orcopolymers thereof, and polyurethanes. In embodiments, the first layeris selected from a woven polymer fabric, a non-woven polymer fabric, apolymer laminate, and a polymer/metal laminate. In some embodiments, thefirst layer has a thickness of about 0.5-10 mil.

In embodiments, the second layer is an adhesive layer. In someembodiments, the adhesive layer is an adhesive tie layer. In someembodiments, the one or more polymers of the second layer has at leastone of (i) a tensile strength of less than about 10 MPa and (ii) anelongation of at least about 50%. In embodiments, the one or morepolymers of the second layer are selected from acrylates, acrylatecopolymers, polyisobutylene, silicone, polystyrene butyl rubber,polyethylene vinyl acetate and copolymers thereof, and plasticizedpolymers. In some embodiments, one or more of the adhesive polymers ofthe second layer have a shear strength that is less or equal to about1-25% of the tensile strength for the polymer. In embodiments, thesecond layer has a thickness of about 0.5-30 mil.

In some embodiments, the third layer is formed of an occlusive orsubstantially occlusive material. In some embodiments, the third layeris comprised of one or more polymers selected from polyethyleneterephthalate (PET), polyethylenes, vinyl acetates or copolymersthereof, polypropylenes, nylon, polystyrenes, polyvinylchloride,polyurethanes, ethylene-vinyl acetate, copolymers thereof, ormixtures/blends thereof. In some embodiments, the third layer iscomprised of a polyethylene terephthalate/ethylene-vinyl acetatelaminate. In other embodiments, the third layer is comprised of apolyethylene terephthalate film. In some embodiments, the third layerhas a thickness of about 1-40 mil. In embodiments, the third layer isattached to an adhesive drug layer comprising one or more drugs.

In embodiments, the first layer, second layer, and third layer arelaminated. In some embodiments, at least the first layer or the thirdlayer is at least partially cut.

In a second aspect, a transdermal patch for delivery of an active agentis provided. In embodiments, the transdermal patch comprises (a) acomposite backing layer comprising: (i) a first layer comprised of apolymer fabric or a polymer film having a stretchability of at leastabout 5% in at least one direction; (ii) a second layer comprised one ormore adhesive polymers; and (iii) a third layer comprised of one or morepolymers, where the first layer, second layer, and third layers arearranged in contact as a composite; (b) an adhesive drug layercomprising the active agent; and (c) a release liner.

In embodiments, the first layer polymer fabric or polymer film iscomprised of one or more polymers selected from polyesters,polyethylenes, polypropylenes, polyvinylchloride, polyethylene vinylacetate or copolymers thereof, and polyurethanes. In embodiments, thefirst layer is selected from an occlusive polymer film, a polymerlaminate, a polymer/metal laminate, a breathable polymer film, a wovenpolymer fabric and a non-woven polymer fabric. In some embodiments, thefirst layer has a thickness of about 0.5-10 mil.

In embodiments, the one or more polymers of the second layer areselected from acrylates, acrylate copolymers, polyisobutylene, silicone,polystyrene butyl rubber, polyethylene vinyl acetate and copolymersthereof, and plasticized polymers. In some embodiments, one or more ofthe adhesive polymers of the second layer have a shear strength that isless or equal to about 1-25% of the tensile strength for the polymer. Insome embodiments, the second layer has a thickness of about 0.5-30 mil.

In some embodiments, the third layer is formed of an occlusive orsubstantially occlusive material. In some embodiments, the third layeris comprised of one or more polymers selected from polyethyleneterephthalate (PET), polyethylenes, vinyl acetates or copolymersthereof, polypropylenes, nylon, polystyrenes, polyvinylchloride,polyurethanes, ethylene-vinyl acetate, copolymers thereof, ormixtures/blends thereof. In some embodiments, the third layer iscomprised of a polyethylene terephthalate/ethylene-vinyl acetatelaminate. In other embodiments, the third layer is comprised of apolyethylene terephthalate film. In embodiments, the third layer has athickness of about 1-40 mil.

In embodiments, the release liner is formed of a material selected froma silicone coated polyethylene terephthalate, a fluorocarbon, afluorocarbon coated polyethylene terephthalate, and a fluorosiliconecoated polyethylene terephthalate.

In a further aspect, a method of transdermally administering an activeagent is provided. In embodiments, the method comprises removing arelease liner from the transdermal patch and adhering the transdermalpatch to the skin of a patient for a period up to about 10 days todeliver the active agent to said patient.

In embodiments, the transdermal patch comprises (a) a composite backinglayer, (b) an adhesive drug layer comprising the active agent; and (c) arelease liner. In embodiments, the composite backing layer comprises afirst layer comprised of a polymer fabric or a polymer film having astretchability of at least about 5% in at least one direction; a secondlayer comprised one or more adhesive polymers; and a third layercomprised of one or more polymers. In embodiments, the first layer,second layer, and third layers are arranged in contact as a composite.

Additional embodiments of the present methods and compositions, and thelike, will be apparent from the following description, drawings,examples, and claims. As can be appreciated from the foregoing andfollowing description, each and every feature described herein, and eachand every combination of two or more of such features, is includedwithin the scope of the present disclosure provided that the featuresincluded in such a combination are not mutually inconsistent. Inaddition, any feature or combination of features may be specificallyexcluded from any embodiment of the present invention. Additionalaspects and advantages of the present invention are set forth in thefollowing description and claims, particularly when considered inconjunction with the accompanying examples and drawings.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an illustration of a transdermal patch having a compositebacking, an agent adhesive layer and a backing layer in accord withembodiments described herein.

FIG. 2 is an illustration of a transdermal patch comprising a layeredcomposite backing in accord with embodiments described herein.

FIG. 3 is an illustration of a composite backing in accord withembodiments described herein.

FIG. 4A is a top view illustration of a backing laminate layer. FIG. 4Bis a top view image of a divided backing layer.

FIG. 5 is a side view illustrating an exemplary composite backingcomprising separate pieces for a first or top layer.

FIG. 6 is an illustration of a bottom-up view of a segmented patch layerin accord with embodiments described herein.

DETAILED DESCRIPTION

I. Definitions

Various aspects now will be described more fully hereinafter. Suchaspects may, however, be embodied in many different forms and should notbe construed as being limited to the embodiments set forth herein;rather, these embodiments are provided so that this disclosure will bethorough and complete, and will fully convey its scope to those skilledin the art.

It is to be understood that, unless otherwise indicated, these aspectsand embodiments are not limited to specific polymers, oligomers,crosslinking agents, additives, manufacturing processes, or adhesiveproducts. It is also to be understood that the terminology used hereinis for the purpose of describing particular embodiments only, and is notintended to be limiting.

Where a range of values is provided, it is intended that eachintervening value between the upper and lower limit of that range andany other stated or intervening value in that stated range isencompassed within the disclosure. For example, if a range of 1 μm to 8μm is stated, it is intended that 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μmare also explicitly disclosed, as well as the range of values greaterthan or equal to 1 μm and the range of values less than or equal to 8μm.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference toa “polymer” includes a single polymer as well as two or more of the sameor different polymers, reference to an “excipient” includes a singleexcipient as well as two or more of the same or different excipients,and the like.

The use of terms of order or importance, including “first” and “second”,is to distinguish and identify individual elements and does not denoteor imply a particular order or importance unless clearly indicated bycontext.

The term “active agent” as used herein refers to a chemical material orcompound suitable for topical or transdermal administration and thatinduces a desired effect. The terms include agents that aretherapeutically effective, prophylactically effective, and cosmeticallyeffective agents. The terms “active agent”, “drug” and “therapeuticagent” are used interchangeably herein.

The term “hydrogel” is used in the conventional sense to refer towater-swellable polymeric matrices that can absorb a substantial amountof water to form elastic gels, wherein “matrices” are three-dimensionalnetworks of macromolecules held together by covalent or noncovalentcrosslinks. Upon placement in an aqueous environment, dry hydrogelsswell to the extent allowed by the degree of cross-linking.

The term “hydrogel composition” refers to a composition that eithercontains a hydrogel or is entirely composed of a hydrogel. As such,“hydrogel compositions” encompass not only hydrogels per se but alsocompositions that not only contain a hydrogel but also contain one ormore non-hydrogel components or compositions, e.g., hydrocolloids, whichcontain a hydrophilic component (which may contain or be a hydrogel)distributed in a hydrophobic phase.

“Matrix” as used herein refers to a solid or semi-solid substanceincluding, but not limited to, a polymeric material, adhesive or gel.The matrix typically serves as a repository or carrier for substancesincluding the therapeutic agent.

“Occlusive” as used herein refers to a material that limits thediffusion rate of moisture vapor and/or oxygen. A “non-occlusive”material allows a higher diffusion rate for moisture vapor and/oroxygen.

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.

The term “skin” as used herein refers to skin or other biologicalmembranes or mucosal tissue, including the interior surface of bodycavities that have a mucosal lining. The term “skin” should beinterpreted as including “mucosal tissue” and vice versa. It will beunderstood by persons of skill in the art that in most or all instancesthe same inventive principles apply to administration through otherbiological membranes such as those which line the interior of the mouth(e.g. oral mucosal membranes), gastro-intestinal tract, blood-brainbarrier, or other body tissues or organs or biological membranes whichare exposed or accessible during surgery or during procedures such aslaparoscopy or endoscopy.

“Substantially” or “essentially” means nearly totally or completely, forinstance, 90-95% or greater of some given quantity.

The term “therapeutically effective amount” as used herein refers to theamount of an active agent that is nontoxic but sufficient to provide thedesired therapeutic effect. The amount that is “effective” will varyfrom subject to subject, depending on the age and general condition ofthe individual, the particular active agent or agents, and the like asknown to those skilled in the art.

The terms “transdermal” or “transdermal delivery” as used herein referto administration of an active agent to a body surface of an individualso that the agent passes through the body surface, e.g., skin, and intothe individual's blood stream (systemic circulation). The term“transdermal” is intended to include transmucosal administration, i.e.,administration of a drug to the mucosal (e.g., sublingual, buccal,vaginal, rectal) surface of an individual so that the agent passesthrough the mucosal tissue and into the individual's blood stream.

The terms “transdermal patch”, “transdermal device” and/or “transdermalsystem” all relate to a layered patch, device or system that providestransdermal delivery of an active agent therefrom. The terms are usedinterchangeably herein.

II. Transdermal Devices and Systems

The systems and devices described herein are designed for prolonged orlong term transdermal administration of an active agent. Thecompositions may be used in devices, patches or systems suitable fortransdermal delivery of the active agent. Reference to a transdermaldevice, system or patch herein applies equally to each of the terms. Thedevices and systems are especially useful for long term delivery of theactive agent from the device. For the long term delivery, the systemmust remain adhered or substantially adhered to the administration siteas delivery of the active agent from the transdermal device requirescontact between the agent containing layer and the administration site(directly or indirectly). Most transdermal patches cannot or do notremain sufficiently adhered to the skin for an extended period of morethan a couple of days. Many commercial patches advise users to replacepatches that peel off the skin or become substantially unadhered. Theadhesion problem becomes greater for larger patch sizes and/or forpatches that are applied for longer durations such as more than 1-3days. Friction between moving skin and the static backing layerincreases shear resistance of the adhesive/drug layer that is adhered tothe stiff backing layer. These patches are either lifted off the skin orbecome buckled up from the skin, causing the patch to lose contact withthe skin. Eventually, this results in patch failure. This friction mayalso lead to skin irritation, particularly along the edges of the patch.The propensity for larger patches to buckle or fail practically limitsthe size of patches. Because the patch size is one factor in the dose ofthe active agent that is delivered, the patch size may also limit thedose and duration of administration of the active agent.

The present transdermal devices and systems provide a transdermal deviceor system that includes a composite backing layer that reduces frictionwithin the device or system and allows for long term wear, larger patchsize, and/or reduced skin irritation.

In some embodiments, the transdermal device, patch or system is usefulfor long term or extended wear or administration. In embodiments, thetransdermal device is suitable for administration of at least about 3days or more. In some embodiments, the transdermal device is suitablefor administration of at least about or up to about 3-14 days. In someembodiments, the transdermal device is suitable for administration up toabout 10-14 days. In some embodiments, the transdermal device issuitable for administration of at least about or up to about 3-5 days,3-7 days, 3-10 days, 5-7 days, 5-10 days, 5-14 days, 6-10 days, 6-14days, 7-10 days, 7-14 days, 8-10 days, 8-14 days, 9-10 days, 9-14 days,or 10-14 days. In some non-limiting embodiments, the transdermal deviceis suitable for administration of at least about or up to about 3 days,4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or 14 days. Bysuitable for administration, it is meant that the device, patch orsystem remains sufficiently adhered to the administration site to allowfor contact of the adhesive drug layer with the skin such that theactive agent is transdermally delivered. In embodiments, the device,patch or system is continuously adhered to the administration site. Insome embodiments, the device, patch or system is substantially adheredto the administration site.

FIG. 1 shows an embodiment of an exemplary transdermal patch, device orsystem, generally designated at 10, having a composite backing layer oroverlay. In this embodiment, the device includes a composite backinglayer 12, an adhesive drug layer 14 and an optional release liner 16.

The backing layer provides a structural element for holding orsupporting the adhesive drug layer. In the discussion of the backinglayer below, it will be appreciated that the discussion applies to thebacking layer as a whole as well as any one or more of the individuallayers of the composite backing layer. The backing layer may be formedof any suitable material as known in the art. In some embodiments, thebacking layer is occlusive or breathable. In some embodiments, thebacking layer is preferably impermeable or substantially impermeable tomoisture by preventing passage of all or substantially all moisture. Inone exemplary embodiment, the barrier layer has an MVTR (moisture vaportransmission rate) of less than about 50 g/m²/day. In some embodiments,the barrier layer has an MVTR of about 0.5-1500 g/m²/day or about 0.5-50g/m²/day. In some specific but not limiting embodiments, the barrierlayer has an MVTR of less than about or about 0.5 g/m²/day, 1 g/m²/day,5 g/m²/day, 10 g/m²/day, 15 g/m²/day, 20 g/m²/day, 25 g/m²/day, 30g/m²/day, 40 g/m²/day, or 50 g/m²/day. In some embodiments, the backinglayer is preferably inert and/or does not absorb components of theadhesive drug layer, including the active agent. In some embodiments,the backing layer preferably prevents release of components of theadhesive drug layer through the backing layer. The backing layer may beflexible, substantially flexible or nonflexible. The backing layer ispreferably at least partially flexible such that the backing layer isable to conform at least partially to the shape of the skin where thepatch is applied. In some embodiments, the backing layer is flexiblesuch that the backing layer conforms to the shape of the skin where thepatch is applied. In some embodiments, the backing layer is sufficientlyflexible to maintain contact at the application site with movement, e.g.skin movement. Typically, at least some of the materials used for thebacking layer should permit the device to follow the contours of theskin or other application site and be worn comfortably on areas of skinsuch as at joints or other points of flexure, that are normallysubjected to mechanical strain with little or no likelihood of thedevice disengaging from the skin due to differences in the flexibilityor resiliency of the skin and the device. In some embodiments, thebacking layer does not affect and/or control the release profile of theactive agent from the device. In some embodiments, the backing layer isnot the predominant factor affecting and/or controlling the releaseprofile of the active agent from the device.

In some embodiments, at least a portion of the transdermal patch has asize or surface area of about 5-200 cm². In some non-limitingembodiments, the transdermal patch has a size or surface area of about5-10 cm², 5-15 cm², 5-20 cm², 5-25 cm², 5-30 cm², 5-40 cm², 5-45 cm²,5-50 cm², 5-60 cm², 5-70 cm², 5-75 cm², 5-80 cm², 5-90 cm², 5-100 cm²,5-125 cm², 5-150 cm², 5-175 cm², 10-15 cm², 10-20 cm², 10-25 cm², 10-30cm², 10-40 cm², 10-45 cm², 10-50 cm², 10-60 cm², 10-70 cm², 10-75 cm²,10-80 cm², 10-90 cm², 10-100 cm², 10-125 cm², 10-150 cm², 10-175 cm²,10-200 cm², 15-20 cm², 15-25 cm², 15-30 cm², 15-40 cm², 15-45 cm², 15-50cm², 15-60 cm², 15-70 cm², 15-75 cm², 15-80 cm², 15-90 cm², 15-100 cm²,15-125 cm², 15-150 cm², 15-175 cm², 15-200 cm², 20-25 cm², 20-30 cm²,20-40 cm², 20-45 cm², 20-50 cm², 20-60 cm², 20-70 cm², 20-75 cm², 20-80cm², 20-90 cm², 20-100 cm², 20-125 cm², 20-150 cm², 20-175 cm², 20-200cm², 25-30 cm², 25-40 cm², 25-45 cm², 25-50 cm², 25-60 cm², 25-70 cm²,25-75 cm², 25-80 cm², 25-90 cm², 25-100 cm², 25-125 cm², 25-150 cm²,25-175 cm², 25-200 cm², 30-40 cm², 30-45 cm², 30-50 cm², 30-60 cm²,30-70 cm², 30-75 cm², 30-80 cm², 30-90 cm², 30-100 cm², 30-125 cm²,30-150 cm², 30-175 cm², 30-200 cm², 40-45 cm², 40-50 cm², 40-60 cm²,40-70 cm², 40-75 cm², 40-80 cm², 40-90 cm², 40-100 cm², 40-125 cm²,40-150 cm², 40-175 cm², 40-200 cm², 45-50 cm², 45-60 cm², 45-70 cm²,45-75 cm², 45-80 cm², 45-90 cm², 45-100 cm², 45-125 cm², 45-150 cm²,45-175 cm², 45-200 cm², 50-60 cm², 50-70 cm², 50-75 cm², 50-80 cm²,50-90 cm², 50-100 cm², 50-125 cm², 50-150 cm², 50-175 cm², 50-200 cm²,60-70 cm², 60-75 cm², 60-80 cm², 60-90 cm², 60-100 cm², 60-125 cm²,60-150 cm², 60-175 cm², 60-200 cm², 70-75 cm², 70-80 cm², 70-90 cm²,70-100 cm², 70-125 cm², 70-150 cm², 70-175 cm², 70-200 cm², 80-90 cm²,80-100 cm², 80-125 cm², 80-150 cm², 80-175 cm², 80-200 cm², 90-100 cm²,90-125 cm², 90-150 cm², 90-175 cm², 90-200 cm², 100-125 cm², 100-150cm², 100-175 cm², 100-200 cm², 125-150 cm², 125-175 cm², 125-200 cm²,150-175 cm², 150-200 cm², or 175-200 cm². In specific, but not limiting,embodiments, the transdermal patch has a size or surface area of about 5cm², 10 cm², 15 cm², 20 cm², 25 cm², 30 cm², 40 cm², 45 cm², 50 cm², 60cm², 70 cm², 75 cm², 80 cm², 90 cm², 100 cm², 125 cm², 150 cm², 175 cm²,or 200 cm². It will be appreciated that different layers of the backingand/or the device may have a different surface area or size. in oneembodiment, at least a portion (e.g. at least one layer) of the backingextends beyond the edge of at least the adhesive drug layer.

The transdermal patch may be prepared to have a thickness such that thedesired amount of drug formulation is contained within the patchincluding the desired components while maintaining a thickness that iswearable and comfortable for the subject. In some embodiments, thetransdermal patch has a thickness of about 2-200 mil including thecomposite backing layer and the adhesive drug layer. In specificnon-limiting embodiments, the transdermal patch has a thickness of about2-10 mil, 2-25 mil, 2-30 mil, 2-40 mil, 2-50 mil, 2-75 mil, 2-80 mil,2-100 mil, 2-125 mil, 2-150 mil, 2-175 mil, 2.5-10 mil, 2.5-25 mil,2.5-30 mil, 2.5-40 mil, 2.5-50 mil, 2.5-75 mil, 2.5-80 mil, 2.5-100 mil,2.5-125 mil, 2.5-150 mil, 2.5-175 mil, 2.5-200 mil, 3-10 mil, 3-25 mil,3-30 mil, 3-40 mil, 3-50 mil, 3-75 mil, 3-80 mil, 3-100 mil, 3-125 mil,3-150 mil, 3-175 mil, 3-200 mil, 5-10 mil, 5-25 mil, 5-30 mil, 5-40 mil,5-50 mil, 5-75 mil, 5-80 mil, 5-100 mil, 5-125 mil, 5-150 mil, 5-175mil, 5-200 mil, 7-10 mil, 7-25 mil, 7-30 mil, 7-40 mil, 7-50 mil, 7-75mil, 7-80 mil, 7-100 mil, 7-125 mil, 7-150 mil, 7-175 mil, 7-200 mil,8-10 mil, 8-25 mil, 8-30 mil, 8-40 mil, 8-50 mil, 8-75 mil, 8-80 mil,8-100 mil, 8-125 mil, 8-150 mil, 8-175 mil, 8-200 mil, 10-25 mil, 10-30mil, 10-40 mil, 10-50 mil, 10-75 mil, 10-80 mil, 10-100 mil, 10-125 mil,10-150 mil, 10-175 mil, 10-200 mil, 25-30 mil, 25-40 mil, 25-50 mil,25-75 mil, 25-80 mil, 25-100 mil, 25-125 mil, 25-150 mil, 25-175 mil,25-200 mil, 30-40 mil, 30-50 mil, 30-75 mil, 30-80 mil, 30-100 mil,30-125 mil, 30-150 mil, 30-175 mil, 30-200 mil, 40-50 mil, 40-75 mil,40-80 mil, 40-100 mil, 40-125 mil, 40-150 mil, 40-175 mil, 40-200 mil,50-75 mil, 50-80 mil, 50-100 mil, 50-125 mil, 50-150 mil, 50-175 mil,50-200 mil, 75-80 mil, 75-100 mil, 75-125 mil, 75-150 mil, 75-175 mil,75-200 mil, 80-100 mil, 80-125 mil, 80-150 mil, 80-175 mil, 80-200 mil,100-125 mil, 100-150 mil, 100-175 mil, 100-200 mil, 125-150 mil, 125-175mil, 125-200 mil, 150-175 mil, 150-200 mil, or 175-200 mil. In specific,but not limiting, embodiments, the transdermal patch has a thickness ofabout 2 mil, 2.5 mil, 3 mil, 4 mil, 5 mil, 7 mil, 7.5 mil, 8 mil, 10mil, 15 mil, 20 mil, 25 mil, 30 mil, 40 mil, 50 mil, 60 mil, 70 mil, 75mil, 80 mil, 90 mil, 100 mil, 125 mil, 150 mil, 175 mil, or 200 mil. Thethickness for the patch describes above may apply to the patch includingthe optional release liner or the patch as applied (including only thebacking and drug layers).

In a first aspect, as seen in FIGS. 2 and 3, the backing layer oroverlay 12 is a composite comprising multiple or several layers to allowmovement within the composite backing/and or the adhesive drug layer 14.The composite layers may be laminated or otherwise adhered as known inthe art. Lamination generally refers to manufacture by layering andadhering materials. In embodiments as shown in FIG. 3, the backing layercomprises a first exterior or top layer 18, a second, middle layer 20,and a third or bottom layer 22. In the embodiment as shown in FIG. 2, atleast the second/middle layer 20 and the third/bottom layer 22 of thecomposite backing as well as the adhesive/drug layer 14, collectivelyindicated at 38, allow for shear yield and/or movement to allowdissipation of movement within the transdermal delivery system. In otherembodiments, at least the first/top layer 18 and the second/middle layer20 of the composite backing allow for shear yield and/or movement toallow dissipation of movement within the transdermal delivery system.

In non-limiting embodiments, the composite layer has a thickness ofabout 2-100 mil. In specific non-limiting embodiments, the compositelayer has a thickness of about 5-10 mil, 5-15 mil, 5-20 mil, 5-25 mil,5-30 mil, 5-40 mil, 5-50 mil, 5-60 mil, 5-70 mil, 5-75 mil, 5-80 mil,5-90 mil, 5-100 mil, 10-15 mil, 10-20 mil, 10-25 mil, 10-30 mil, 10-40mil, 10-50 mil, 10-60 mil, 10-70 mil, 10-75 mil, 10-80 mil, 10-90 mil,10-100 mil, 15-20 mil, 15-25 mil, 15-30 mil, 15-40 mil, 15-50 mil, 15-60mil, 15-70 mil, 15-75 mil, 15-80 mil, 15-90 mil, 15-100 mil, 20-25 mil,20-30 mil, 20-40 mil, 20-50 mil, 20-60 mil, 20-70 mil, 20-75 mil, 20-80mil, 20-90 mil, 20-100 mil, 25-30 mil, 25-40 mil, 25-50 mil, 25-60 mil,25-70 mil, 25-75 mil, 25-80 mil, 25-90 mil, 25-100 mil, 30-40 mil, 30-50mil, 30-60 mil, 30-70 mil, 30-75 mil, 30-80 mil, 30-90 mil, 30-100 mil,40-50 mil, 40-60 mil, 40-70 mil, 40-75 mil, 40-80 mil, 40-90 mil, 40-100mil, 50-60 mil, 50-70 mil, 50-75 mil, 50-80 mil, 50-90 mil, 50-100 mil,50-70 mil, 50-75 mil, 50-80 mil, 50-90 mil, 50-100 mil, 60-70 mil, 60-75mil, 60-80 mil, 60-90 mil, 60-100 mil, 70-75 mil, 70-80 mil, 70-90 mil,70-100 mil, 75-80 mil, 75-90 mil, 75-100 mil, 80-90 mil, 80-100 mil, or90-100 mil.

The first layer is a protective outer layer which serves at least toprotect the patch. In some embodiments, the first layer overlays oroverhangs at least one edge of at least one of the second layer, thirdlayer, or the adhesive/drug layer. In embodiments, the first layer iscomprised of a woven or non-woven polymer fabric, a polymer film, anocclusive polymer film, a polymer laminate and a polymer/metal laminate.A woven fabric is generally produced from warp and weft polymeric ornatural fibers. Exemplary woven or non-woven fabrics are polyesterfabrics. One exemplary woven fabric is a bi-elastic polyester fabricsuch as the KOB 053 available from Karl Otto GmbH & Co. In someembodiments, the polymer film is an elastic polymer film. In someembodiments, the first layer is comprised of stretchable polymers. Insome embodiments, the first layer is comprised of one or more polymershaving a low shear strength or resistance. The shear strength may bemeasured by any methods as known in the art. Some exemplary methods oftesting or measuring shear strength include the punch technique or testand the losipescu test as known to those skilled in the art. In someembodiments, the shear strength may be measured using a viscometer.

Suitable polymers are known in the art and include elastomers,polyesters, polyethylenes, polypropylenes, polyurethanes polyetheramides and copolymers thereof. In some embodiments, the polymer ispolyethylene vinyl acetate, polyvinylchloride or copolymers thereof. Insome embodiments, the first layer is comprised of one or more ofpolyethylene terephthalate, polyvinyl acetate, polyvinylidene chloride,polyvinylchloride, and polyethylene vinyl acetate or copolymers thereof.Polymer/metal laminates are known in the art and include aluminumlaminates and tin laminates, among others. In some embodiments, thefirst layer is comprised of a laminate. In one non-limiting embodiment,the first layer is comprised of a polyethylene and polyester laminatesuch as the laminate sold under the name Scotchpak™ #9723. In someembodiments, the first layer is formed of a polyurethane film, athermoplastic polyester elastomer such as a Hytrel® film available fromDuPont®, or a polyethylene vinyl acetate film. In some embodiments, atleast the first layer of the backing layer is occlusive.

In some embodiments, the first layer is a stretchable, elastic and/orflexible layer comprised of one or more polymers having a stretchabilityand/or elasticity of at least about 5% in at least one direction. Inthis embodiment, the first layer, along with the second or middle layerabsorbs the stress of the movement of the adhesive drug layer or deviceagainst the skin or other administration site. In some embodiments, thefirst layer is comprised of one or more stretchable polymers having astretchability and/or elasticity of at least about 5% or at least about10% in at least one direction. The stretchability may be ascertained byany suitable means as known in the art. In some embodiments, thestretchability is determined at room temperature or at approximately20-25° C. In embodiments, the first layer is comprised of one or morestretchable polymers having a stretchability and/or elasticity of atleast about 5-50%. In some embodiments, the first layer is comprised ofone or more stretchable polymers having a stretchability and/orelasticity of at least about 5-40%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%,10-50%, 10-40%, 10-30%, 10-25%, 10-20%, 10-15%, 15-50%, 15-40%, 15-30%,15-25%, 15-20%, 20-50%, 20-40%, 20-30%, 20-25%, 25-50%, 25-40%, 25-30%,30-50%, 30-40%, or 40-50%. In specific, but not limiting embodiments,the first layer is comprised of one or more stretchable polymers havinga stretchability and/or elasticity of at least about 5%, 10%, 15%, 20%,25%, 30%, 40%, or 50%. In some embodiments, the first layer isstretchable, but not elastic. In other embodiments, the first layer isrelatively stiff.

In embodiments, the first layer has a thickness of about 0.5-15 mil. Innon-limiting embodiments, the first layer has a thickness of betweenabout 0.5-0.75 mil, 0.5-1 mil, 0.5-1.5 mil, 0.5-2 mil, 0.5-2.5 mil,0.5-3 mil, 0.5-4 mil, 0.5-5 mil, 0.5-6 mil, 0.5-7 mil, 0.5-8 mil, 0.5-9mil, 0.5-10 mil, 0.75-1 mil, 0.75-1.5 mil, 0.75-2 mil, 0.75-2.5 mil,0.75-3 mil, 0.75-4 mil, 0.75-5 mil, 0.75-6 mil, 0.75-7 mil, 0.75-8 mil,0.75-9 mil, 0.75-10 mil, 0.75-15 mil, 1-1.5 mil, 1-2 mil, 1-2.5 mil, 1-3mil, 1-4 mil, 1-5 mil, 1-6 mil, 1-7 mil, 1-8 mil, 1-9 mil, 1-10 mil,1-15 mil, 1.5-2 mil, 1.5-2.5 mil, 1.5-3 mil, 1.5-4 mil, 1.5-5 mil, 1.5-6mil, 1.5-7 mil, 1.5-8 mil, 1.5-9 mil, 1.5-10 mil, 1.5-15 mil, 2-2.5 mil,2-3 mil, 2-4 mil, 2-5 mil, 2-6 mil, 2-7 mil, 2-8 mil, 2-9 mil, 2-10 mil,2-15 mil, 2.5-3 mil, 2.5-4 mil, 2.5-5 mil, 2.5-6 mil, 2.5-7 mil, 2.5-8mil, 2.5-9 mil, 2.5-10 mil, 2.5-15 mil, 3-4 mil, 3-5 mil, 3-6 mil, 3-7mil, 3-8 mil, 3-9 mil, 3-10 mil, 3-15 mil, 4-5 mil, 4-6 mil, 4-7 mil,4-8 mil, 4-9 mil, 4-10 mil, 4-15 mil, 5-6 mil, 5-7 mil, 5-8 mil, 5-9mil, 5-10 mil, 5-15 mil, 6-7 mil, 6-8 mil, 6-9 mil, 6-10 mil, 6-15 mil,7-8 mil, 7-9 mil, 7-10 mil, 7-15 mil, 8-9 mil, 8-10 mil, 8-15 mil, 9-10mil, 9-15 mil or 10-15 mil. In specific non-limiting embodiments, thefirst layer has a thickness of about 0.5 mil, 0.75 mil, 1 mil, 1.5 mil,2 mil, 3 mil, 4 mil, 5 mil, 6 mil, 7 mil, 8 mil, 9 mil, 10 mil or 15mil.

The composite backing layer further comprises a second or middle layer20 adjacent the first or top layer. The second layer is preferably anadhesive, tie or binding layer positioned between the first and thirdlayers. The second layer serves to adhere, attach or bind the first andthird layers. In embodiments, one of the first or third layers isrelatively stiff and/or stationary and the other of the first and thirdlayer is flexible and/or elastic. The second layer, along with theflexible or relatively flexible layer absorbs the stress of the adhesivedrug layer against the skin or other administration site. Inembodiments, the second layer is comprised of polymers having a tensileor yield strength of less than about 5 MPa or about 10 MPa. The tensilestrength is a measurement of the force required per unit area (MPa) atthe break point of the polymer. In some embodiments, the second layer iscomprised of one or more polymers having a tensile strength of less thanabout 5-10 MPa. In some embodiments, the second layer is comprised ofone or more polymers having a tensile strength of less than about 6-10MPa, 7-10 MPa, 8-10 MPa, or 9-10 MPa. In some embodiments, the secondlayer is comprised of polymers such that the second layer as a whole hasa tensile strength of less than about 10 MPa. The tensile or yieldstrength may be ascertained by any suitable means as known in the art.In one embodiment, the tensile or yield strength is determined by theASTM D882 test which comprising pulling a polymer sample from both endsto determine the force required at the yield or break point. In someembodiments, the tensile strength is the tensile strength at roomtemperature or at approximately 20-25° C.

In embodiments, the second layer is comprised of polymers having anelongation of not less than or at least about 10%. In some embodiments,the second layer is comprised of polymers having an elongation of notless than or at least about 50%. The elongation refers to the percentageof elongation before the polymer breaks under an applied strain. Inembodiments, the % elongation is the final length (L) of the polymer orpolymer material after stretching, minus the initial length (L_(i))divided by the initial length. The % elongation may be ascertained byany suitable means as known in the art. In some embodiments, the %elongation is determined at room temperature or at approximately 20-25°C. In some embodiments, the second layer is comprised of polymers suchthat the second layer as a whole has a % elongation of at least about ornot less than about 10% or about 50%. In some embodiments, the secondlayer is comprised of one or more polymers having a % elongation of atleast about 10-500%. In some embodiments, the second layer is comprisedof one or more polymers having a % elongation of at least about 10-75%,10-100%, 10-150%, 10-200%, 10-250%, 10-300%, 10-400%, 50-75%, 50-100%,50-150%, 50-200%, 50-250%, 50-300%, 50-400%, 50-500%, 75-100%, 75-150%,75-200%, 75-250%, 75-300%, 75-400%, 75-500%, 100-150%, 100-200%,100-250%, 100-300%, 100-400%, 100-500%, 150-200%, 150-250%, 150-300%,150-400%, 150-500%, 200-250%, 200-300%, 200-400%, 200-500%, 250-300%,250-400%, 250-500%, 300-400%, 300-500%, 400-500% or more.

In some embodiments, the second layer is comprised of one or morepolymers having a low shear strength. Shear strength refers to thepolymer's ability to resist forces that cause the internal structure toslide against itself. In some embodiments, the shear strength isexpressed in terms of a percentage of the tensile strength of thepolymer(s). In some non-limiting embodiments, one or more of thepolymers of the second layer have a shear strength that is or is lessthan about 1-25% of its tensile strength. In some embodiments, one ormore of the polymers has a shear strength that is or is less than about1-20%, 1-15%, 1-10%, 1-5%, 5-25%, 5-20%, 5-15%, 5-10%, 10-25%, 10-20%,10-15%, 15-25%, 15-20%, or 20-25% of the tensile strength for thepolymer. In some specific, but not limiting embodiments, one or more ofthe polymers has a shear strength that is or is less than about 1%, 5%,10%, 15%, 20%, 25%, 30%, or 40% of the tensile strength for the polymer.In some embodiments, the shear strength is about or less than about0.1-15 MPa. In some embodiments, the shear strength is about or lessthan about 0.1-10 MPa, 0.1-9 MPa, 0.1-8 MPa, 0.1-7 MPa, 0.1-6 MPa, 0.1-5MPa, 0.1-4 MPa, 0.1-3 MPa, 0.1-2 MPa, 0.1-1 MPa, 0.1-0.5 MPa, 0.5-15MPa, 0.5-10 MPa, 0.5-9 MPa, 0.5-8 MPa, 0.5-7 MPa, 0.5-6 MPa, 0.5-5 MPa,0.5-4 MPa, 0.5-3 MPa, 0.5-2 MPa, 0.5-1 MPa, 1-15 MPa, 1-10 MPa, 1-9 MPa,1-8 MPa, 1-7 MPa, 1-6 MPa, 1-5 MPa, 1-4 MPa, 1-3 MPa, 1-2 MPa, 2-15 MPa,2-10 MPa, 2-9 MPa, 2-8 MPa, 2-7 MPa, 2-6 MPa, 2-5 MPa, 2-4 MPa, 2-3 MPa,3-15 MPa, 3-10 MPa, 3-9 MPa, 3-8 MPa, 3-7 MPa, 3-6 MPa, 3-5 MPa, 3-4MPa, 4-15 MPa, 4-10 MPa, 4-9 MPa, 4-8 MPa, 4-7 MPa, 4-6 MPa, 4-5 MPa,5-15 MPa, 5-10 MPa, 5-9 MPa, 5-8 MPa, 5-7 MPa, 5-6 MPa, 6-15 MPa, 6-10MPa, 6-9 MPa, 6-8 MPa, 6-7 MPa, 7-15 MPa, 7-10 MPa, 7-9 MPa, 7-8 MPa,8-15 MPa, 8-10 MPa, 8-9 MPa, 9-15 MPa, 9-10 MPa, or 10-15 MPa.

In embodiments, the second layer is an adhesive layer. In someembodiments, the second layer is an adhesive tie layer.

In embodiments, the one or more polymers are selected from acrylates andacrylate copolymers, polyisobutylenes, silicone, polystyrene butylrubber, polyethylene vinyl acetate and copolymers thereof. In someembodiments, the second layer is comprised of an adhesive selected fromacrylic adhesives, polyisobutylene adhesives, or silicone adhesives. Insome embodiments, the adhesive is a pressure sensitive adhesive. In someembodiments, the second layer is comprised of plasticized polymers.

In embodiments, the second layer has a thickness of about 0.5-30 mil. Innon-limiting embodiments, the second layer has a thickness of betweenabout 0.5-0.75 mil, 0.5-1 mil, 0.5-1.5 mil, 0.5-2 mil, 0.5-2.5 mil,0.5-3 mil, 0.5-4 mil, 0.5-5 mil, 0.5-6 mil, 0.5-7 mil, 0.5-8 mil, 0.5-9mil, 0.5-10 mil, 0.5-15 mil, 0.5-20 mil, 0.5-25 mil, 0.75-1 mil,0.75-1.5 mil, 0.75-2 mil, 0.75-2.5 mil, 0.75-3 mil, 0.75-4 mil, 0.75-5mil, 0.75-6 mil, 0.75-7 mil, 0.75-8 mil, 0.75-9 mil, 0.75-10 mil,0.75-15 mil, 0.75-20 mil, 0.75-25 mil, 0.75-30 mil, 1-1.5 mil, 1-2 mil,1-2.5 mil, 1-3 mil, 1-4 mil, 1-5 mil, 1-6 mil, 1-7 mil, 1-8 mil, 1-9mil, 1-10 mil, 1-15 mil, 1-20 mil, 1-25 mil, 1-30 mil, 1.5-2 mil,1.5-2.5 mil, 1.5-3 mil, 1.5-4 mil, 1.5-5 mil, 1.5-6 mil, 1.5-7 mil,1.5-8 mil, 1.5-9 mil, 1.5-10 mil, 1.5-15 mil, 1.5-20 mil, 1.5-25 mil,1.5-30 mil, 2-2.5 mil, 2-3 mil, 2-4 mil, 2-5 mil, 2-6 mil, 2-7 mil, 2-8mil, 2-9 mil, 2-10 mil, 2-15 mil, 2-20 mil, 2-25 mil, 2-30 mil, 2.5-3mil, 2.5-4 mil, 2.5-5 mil, 2.5-6 mil, 2.5-7 mil, 2.5-8 mil, 2.5-9 mil,2.5-10 mil, 2.5-15 mil, 2.5-20 mil, 2.5-25 mil, 2.5-30 mil, 3-4 mil, 3-5mil, 3-6 mil, 3-7 mil, 3-8 mil, 3-9 mil, 3-10 mil, 3-15 mil, 3-20 mil,3-25 mil, 3-30 mil, 4-5 mil, 4-6 mil, 4-7 mil, 4-8 mil, 4-9 mil, 4-10mil, 4-15 mil, 4-20 mil, 4-25 mil, 4-30 mil, 5-4 mil, 5-5 mil, 5-6 mil,5-7 mil, 5-8 mil, 5-9 mil, 5-10 mil, 5-15 mil, 5-20 mil, 5-25 mil, 5-30mil, 6-7 mil, 6-8 mil, 6-9 mil, 6-10 mil, 6-15 mil, 6-20 mil, 6-25 mil,6-30 mil, 7-8 mil, 7-9 mil, 7-10 mil, 7-15 mil, 7-20 mil, 7-25 mil, 7-30mil, 8-9 mil, 8-10 mil, 8-15 mil, 8-20 mil, 8-25 mil, 8-30 mil, 9-10mil, 9-15 mil, 9-20 mil, 9-25 mil, 9-30 mil, 10-15 mil, 10-20 mil, 10-25mil, 10-30 mil, 15-20 mil, 15-25 mil, 15-30 mil, 20-25 mil, 20-30 mil,or 25-30 mil. In specific non-limiting embodiments, the second layer hasa thickness of about 0.5 mil, 0.75 mil, 1 mil, 1.5 mil, 2 mil, 3 mil, 4mil, 5 mil, 6 mil, 7 mil, 8 mil, 9 mil, 10 mil, 15 mil, 20 mil, 25 mil,or 30 mil.

The composite backing layer further comprises a third or bottom layeradjacent the second or middle layer. In some embodiments, the thirdlayer is a stretchable and/or flexible layer. In embodiments, the thirdlayer, along with the second or middle layer absorbs the stress of themovement of the adhesive drug layer against the skin or otheradministration site. In some embodiments, the third layer is comprisedof one or more stretchable polymers having a stretchability and/orelasticity of at least about 5% or at least about 10% in at least onedirection. The stretchability may be ascertained by any suitable meansas known in the art. In some embodiments, the stretchability isdetermined at room temperature or at approximately 20-25° C. Inembodiments, the third layer is comprised of one or more stretchablepolymers having a stretchability or elasticity of at least about 5-50%.In some embodiments, the third layer is comprised of one or morestretchable polymers having a stretchability or elasticity of at leastabout 5-40%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-50%, 10-40%, 10-30%,10-25%, 10-20%, 10-15%, 15-50%, 15-40%, 15-30%, 15-25%, 15-20%, 20-50%,20-40%, 20-30%, 20-25%, 25-50%, 25-40%, 25-30%, 30-50%, 30-40%, or40-50%. In specific, but not limiting embodiments, the third layer iscomprised of one or more stretchable polymers having a stretchability orelasticity of at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, or 50%.

In other embodiments, the third layer is relatively stiff as compared toat least one of the first or second layers.

In some embodiments, the third layer is occlusive or substantiallyocclusive. In other embodiments, the third layer is breathable.

In embodiments, the third layer has a thickness of about 1-40 mil. Innon-limiting embodiments, the third layer has a thickness of betweenabout 1-1.5 mil, 1-2 mil, 1-3 mil, 1-4 mil, 1-5 mil, 1-10 mil, 1-15 mil,1-20 mil, 1-25 mil, 1-30 mil, 1-35 mil, 1.5-2 mil, 1.5-3 mil, 1.5-4 mil,1.5-5 mil, 1.5-10 mil, 1.5-15 mil, 1.5-20 mil, 1.5-25 mil, 1.5-30 mil,1.5-35 mil, 1.5-40 mil, 2-3 mil, 2-4 mil, 2-5 mil, 2-10 mil, 2-15 mil,2-20 mil, 2-25 mil, 2-30 mil, 2-35 mil, 2-40 mil, 3-4 mil, 3-5 mil, 3-10mil, 3-15 mil, 3-20 mil, 3-25 mil, 3-30 mil, 3-35 mil, 3-40 mil, 4-5mil, 4-10 mil, 4-15 mil, 4-20 mil, 4-25 mil, 4-30 mil, 4-35 mil, 4-40mil, 5-10 mil, 5-15 mil, 5-20 mil, 5-25 mil, 5-30 mil, 5-35 mil, 5-40mil, 10-15 mil, 10-20 mil, 10-25 mil, 10-30 mil, 10-35 mil, 10-40 mil,15-20 mil, 15-25 mil, 15-30 mil, 15-35 mil, 15-40 mil, 20-25 mil, 20-30mil, 20-35 mil, 20-40 mil, 25-30 mil, 25-35 mil, 25-40 mil, 30-35 mil,30-40 mil, or 35-40 mil. In specific, but not limiting embodiments, thethird layer has a thickness of about 1 mil, 1.5 mil, 2 mil, 3 mil, 4mil, 5 mil, 10 mil, 15 mil, 20 mil, 25 mil, 30 mil, 35 mil, or 40 mil.

In embodiments, the third layer is a non-woven or woven fabric formed ofsynthetic or natural fibers. In embodiments, the synthetic fibers arecomprised of one or more polymer fibers. In embodiments, the naturalfibers are comprised of at least one of cotton or silk. In otherembodiments, the third layer is a polymer film, polymer laminate, orpolymer matrix. In embodiments, the polymer is selected from one or moreof polyesters such as polyethylene terephthalate (PET), polyethylenes,vinyl acetates or copolymers thereof, polypropylenes, nylon,polystyrenes, polyvinylchloride, polyurethanes, ethylene-vinyl acetate,copolymers thereof, or mixtures/blends thereof. In embodiments, thethird layer is a polymer film comprised of a polyethyleneterephthalate/ethylene-vinyl acetate laminate. In other embodiments, thethird layer is comprised of polyethylene terephthalate. The third layeris attached or affixed to an adhesive/drug layer using any suitablemeans. In some embodiments, the third layer is affixed or attached tothe adhesive/drug layer using a suitable adhesive.

Example 1 describes preparation of an exemplary transdermal deliverysystem comprising a composite backing layer. A stretchable or flexiblepolymer layer is laminated onto an occlusive backing using an adhesive.An adhesive formulation is prepared, coated onto a release liner and theformulation is laminated onto the polymer side of the composite backinglaminate. Example 4 describes preparation of a further exemplarytransdermal delivery system comprising a composite backing layer. Astretchable, woven fabric is laminated onto a polymer film using anadhesive. An adhesive drug formulation is prepared, coated onto arelease liner and the formulation is laminated onto the polymer filmside of the composite backing laminate.

In a second aspect, one or more layers of the composite backing is atleast partially cut, incised or divided. In some embodiments, at leastone layer comprises multiple cuts, incisions, or divisions through thelayer such that at least one layer of the composite comprises several,separate pieces. FIG. 5 is a side view illustrating an exemplarycomposite backing comprising separate pieces for a first or top layer.In this aspect, the composite backing 26 comprises a first layer 28, asecond adhesive layer 30, and a third layer 32. Any combination or allof the layers of the composite backing may be at least partially cut,incised or divided. In embodiments, at least one of the first layer orthe third layer is at least partially cut, incised or divided.

As seen FIG. 4A, one or more of layers of the composite backing is atleast partially cut, incised or divided. In some embodiments, at leastthe third layer 32 is at least partially cut, incised or divided. In theembodiment as shown in FIGS. 4A-4B, the third layer is at leastpartially cut, incised or divided such that the third layer is comprisedof a plurality of portions or pieces. These cuts may be formed partiallyor completely through the layer. In an embodiment, the layer is kiss cutsuch that at least one layer is cut while at least one of the layers(e.g. an elastic, flexible or stretchable layer) remains at leastpartially intact. In embodiments, the elastic or flexible polymer layerholds the layer comprising the cuts or incisions. In some embodiments,both the elastic, flexible or stretchable layer and the adhesive layersare at least partially intact. FIG. 4A shows an exemplary grid patternfor the cuts or incisions 36. In some embodiments, the cut layer iscomprised of individually separated pieces of material 34 formed by thecuts in the layer material. The separate pieces may be any appropriateshape or form. In embodiments, the separated pieces are rectangular orsquare. It will be appreciated that the cuts may be regular or irregularin shape. In some embodiments, one or more of the pieces are connectedat one or more connection regions. It will further be appreciated thatthe resulting pieces may be the same or different shapes. FIG. 4B showsa layer formed of individual rectangular pieces of material. In someembodiments, the cut layer is formed of multiple pieces of a relativelystiff material as described above. Motion of the relatively stiff layerwithin the composite and/or against the skin will be dissipated at thecuts. The layer comprising the cuts/pieces will behave like multiplepatches of smaller area applied. Where the cut layer is formed ofseparate pieces, the layer is conformable and/or stretchable along withthe movement of skin. Further, the adhesion of each piece helps anadjacent piece because they are held or adhered together similar to acontinuous layer.

In some embodiments, each piece of the cut layer has a surface area ofbetween about 5-50 cm². In some embodiments, each piece of the cut layerhas a surface area of between about 10-30 cm². In some embodiments, eachpiece has a surface area of about 5 cm², 10 cm², 15 cm², 20 cm², 25 cm²,30 cm², 35 cm², 40 cm², 45 cm², or 50 cm². In some embodiments, thepieces of the layer may comprise a similar size. In other embodiments,the pieces of the layer comprise different sizes.

In some embodiments, the cuts, incisions or divisions extend at leastpartially along a planar surface of at least one layer of the compositebacking. FIG. 6 is a top down view of a device as described herein insome embodiments. As seen in this embodiment, the cuts, incisions ordivisions 4 extend along a portion of one or more layers 42 of thedevice, but do not extend across or along the entirety of the layer. Inthis embodiment, the cuts, incisions or divisions do not intersect.Instead, the layer(s) are intact at one or more of the edges and/or theareas where cross-wise cuts, incisions or divisions would intersect 46.Rather than being separate pieces, the partially cut portions of thelayer 50 are at least partially connected. This embodiment, furthershows the overhang of the first layer 40.

Example 2 describes preparation of an exemplary layer comprising adiscretely cut layer. A flexible polymer material is applied to acarrier formed of paper or other inert material. The carrier serves as asubstrate to form the discretely cut layer. In embodiments, the flexiblepolymer is as described above including, but not limited to, a thin(0.5-1.0 mil) polyurethane film. An occlusive material is applied to theflexible polymer material using a suitable adhesive as known in the art.In some embodiments, the adhesive is selected from a polyisobutylene(PIB), an acrylate, or a silicone adhesive or binding agent. Theresulting laminate comprises the carrier, flexible polymer, adhesive,and occlusive material. The laminate is at least partially cut such thatthe occlusive layer is separated into separated pieces. At least aportion of the flexible polymer layer remains intact.

Example 3 describes preparation of a transdermal delivery system using acomposite backing layer comprising an occlusive layer kiss-cut intorectangular pieces.

The device includes at least one adhesive/drug layer 14 adjacent thecomposite backing layer 12. In embodiments, the adhesive layer is anadhesive matrix comprising the active agent as described above. Theadhesive layer adheres to the backing layer and/or skin at theadministration site. Preferably, the adhesive layer 14 is positionedadjacent the third or bottom layer 22 of the composite backing 12. Theadhesive layer matrix serves to release the active agent to the skin aswell as secure the patch to the skin.

In an embodiment, the adhesive/drug layer is an adhesivehydrogel-containing composition as described in U.S. Pat. No. 8,728,445,which is incorporated herein by reference. One suitablehydrogel-containing composition is comprised of a single, continuoushydrophilic phase. Another suitable composition comprises adiscontinuous hydrophobic phase and a hydrophilic phase that is eithercontinuous or discontinuous. In an embodiment, the hydrogel compositioncomprises a discontinuous hydrophobic phase comprising at least onehydrophobic polymer, a plasticizer such as an elastomer, a tackifyingresin and/or other excipients; and a hydrophilic phase comprised of atleast one crosslinked hydrophilic polymer.

The hydrophobic polymer may be a hydrophobic pressure-sensitive adhesive(PSA) polymer. In some embodiments, the hydrophobic polymer is athermosetting polymer. In embodiments, the hydrophobic PSA polymers arecrosslinked butyl rubbers, wherein a “butyl rubber,” as well known inthe art, is an isoprene-isobutylene copolymer typically having anisoprene content in the range of about 0.5 to 3 wt %, or a vulcanized ormodified version thereof, e.g., a halogenated (brominated orchlorinated) butyl rubber. In some embodiments, the hydrophobic PSApolymer is butyl rubber crosslinked with polyisobutylene. Other suitablehydrophobic polymers include, for example, natural rubber adhesives,vinyl ether polymers, polysiloxanes, polyisoprene, butadieneacrylonitrile rubber, polychloroprene, atactic polypropylene, andethylene-propylene-diene terpolymers (also known as “EPDM” or “EPDMrubber”) (available as Trilene® 65 and Trilene® 67 from UniroyalChemical Co., Middlebury, Conn.). Still other suitable hydrophobic PSAswill be known to those of ordinary skill in the art and/or are describedin the pertinent texts and literature. See, for example, the Handbook ofPressure-Sensitive Adhesive Technology, 2nd Ed., Satas, Ed. (New York:Von Nostrand Reinhold, 1989). In some particular embodiments, thehydrophobic polymers are the crosslinked butyl rubbers available in theKalar® series from Elementis Specialties, Inc. (Hightstown, N.J.),including Kalar® 5200, Kalar® 5215, Kalar® 5246, and Kalar® 5275.

In some embodiments, the hydrophobic phase comprises a plasticizer. By“plasticizer” is meant that the component tends to decrease the glasstransition temperature of the hydrophobic polymer and/or reduce its meltviscosity. Suitable plasticizing elastomers are natural and syntheticelastomeric polymers, including, for example, AB, ABA, and “multiarmed”(AB)x block copolymers, where for example, A is a polymerized segment or“block” comprising aryl-substituted vinyl monomers, preferably styrene,α-methyl styrene, vinyl toluene, and the like, B is an elastomeric,conjugated polybutadiene or polyisoprene block, and x has a value of 3or more. In some embodiments, the plasticizer is an elastomer includingbutadiene-based and isoprene-based polymers, particularlystyrene-butadiene-styrene (SBS), styrene-butadiene (SB),styrene-isoprene-styrene (SIS), and styrene-isoprene (SI) blockcopolymers, where “S” denotes a polymerized segment or “block” ofstyrene monomers, “B” denotes a polymerized segment or block ofbutadiene monomers, and “I” denotes a polymerized segment or block ofisoprene monomers. Other suitable elastomers include radial blockcopolymers having a SEBS backbone (where “E” and “B” are, respectively,polymerized blocks of ethylene and butylene) and I and/or SI arms.Natural rubber (polyisoprene) and synthetic polyisoprene can also beused.

In some embodiments, the hydrophobic phase comprises a tackifying resin.The tackifying resin may be a relatively low molecular weight resin(weight average molecular weight generally less than about 50,000)having a fairly high glass transition temperature. Tackifying resinsinclude, for example, rosin derivatives, terpene resins, and syntheticor naturally derived petroleum resins. In some embodiments, thetackifying resin is selected from the group of non-polar tackifyingresins, such as Regalrez® 1085 (a hydrogenated hydrocarbon resin) andRegalite® Resins such as Regalite® 1900, available from Hercules,Escorez 1304 (also a hydrocarbon resins) and Escorez® 1102 availablefrom Exxon Chemical Company, Wingtack® 95 (a synthetic polyterpeneresin), or Wingtack® 85, available from Goodyear Tire and Rubber.

In some embodiments, the hydrophobic phase comprises an optionalantioxidant which serves to enhance the oxidative stability of thehydrogel composition. Other suitable plasticizers, tackifiers, andantioxidants are known in the art such as those described in U.S. Pat.No. 8,728,445, which is incorporated herein by reference.

In some embodiments, the composition comprises a discontinuoushydrophilic phase comprised of at least one crosslinked hydrophilicpolymer that is insoluble in water under standard conditions of storageand use, but is water-swellable. In embodiments, the degree ofcrosslinking is selected so that the polymer will not melt duringmanufacture of the composition. Suitable hydrophilic polymers include,but are not limited to: crosslinked cellulosic polymers (such ascrosslinked sodium carboxymethylcellulose); crosslinked acrylatepolymers and copolymers; carbomers, i.e., hydroxylated vinylic polymersalso referred to as “interpolymers,” which are prepared by crosslinkinga monoolefinic acrylic acid monomer with a polyalkyl ether of sucrose(commercially available under the trademark Carbopol® from the B. F.Goodrich Chemical Company); crosslinked acrylamide-sodium acrylatecopolymers; gelatin; vegetable polysaccharides, such as alginates,pectins, carrageenans, or xanthan; starch and starch derivatives; andgalactomannan and galactomannan derivatives. One particular crosslinkedhydrophilic polymer is crosslinked sodium CMC, available as Aquasorb®A500 from Aqualon, a division of Hercules, Inc.

In some embodiments, the composition comprises a continuous hydrophilicphase. The continuous hydrophilic phase comprises a water-swellable,water-insoluble polymer, a blend of a hydro hydrophilic polymer and acomplementary oligomer capable of hydrogen bonding thereto, and anoptional low molecular weight plasticizer.

The water-swellable, water-insoluble polymer is generally capable of atleast some degree of swelling when immersed in an aqueous liquid but isinsoluble in water within a selected pH range, generally up to a pH ofat least about 7.5 to 8.5. The polymer may be comprised of a celluloseester, for example, cellulose acetate, cellulose acetate propionate(CAP), cellulose acetate butyrate (CAB), cellulose propionate (CP),cellulose butyrate (CB), cellulose propionate butyrate (CPB), cellulosediacetate (CDA), cellulose triacetate (CTA), or the like. Thesecellulose esters are described in U.S. Pat. Nos. 1,698,049, 1,683,347,1,880,808, 1,880,560, 1,984,147, 2,129,052, and 3,617,201, and may beprepared using techniques known in the art or obtained commercially.Commercially available cellulose esters suitable herein include CA 320,CA 398, CAB 381, CAB 551, CAB 553, CAP 482, CAP 504, all available fromEastman Chemical Company, Kingsport, Tenn. Such cellulose esterstypically have a number average molecular weight of between about 10,000and about 75,000. Other suitable water-swellable polymers are known inthe art as described, for example, in U.S. Pat. No. 8,728,445,incorporated by reference herein.

The hydrogel composition may also include conventional additives such asfillers, preservatives, pH regulators, softeners, thickeners, pigments,dyes, refractive particles, stabilizers, toughening agents,detackifiers, pharmaceutical agents, and permeation enhancers. In thoseembodiments wherein adhesion is to be reduced or eliminated,conventional detackifying agents may also be used. These additives, andamounts thereof, are selected in such a way that they do notsignificantly interfere with the desired chemical and physicalproperties of the hydrogel composition.

Absorbent fillers may be advantageously incorporated to control thedegree of hydration when the adhesive is on the skin or other bodysurface. Such fillers can include microcrystalline cellulose, talc,lactose, kaolin, mannitol, colloidal silica, alumina, zinc oxide,titanium oxide, magnesium silicate, magnesium aluminum silicate,hydrophobic starch, calcium sulfate, calcium stearate, calciumphosphate, calcium phosphate dihydrate, woven and non-woven paper andcotton materials. Other suitable fillers are inert, i.e., substantiallynon-adsorbent, and include, for example, polyethylenes, polypropylenes,polyurethane polyether amide copolymers, polyesters and polyestercopolymers, nylon and rayon. A preferred filler is colloidal silica,e.g., Cab-O-Sil® (Cabot Corporation, Boston, Mass.).

Preservatives include, by way of example, p-chloro-m-cresol, phenylethylalcohol, phenoxyethyl alcohol, chlorobutanol, 4-hydroxybenzoic acidmethylester, 4-hydroxybenzoic acid propylester, benzalkonium chloride,cetylpyridinium chloride, chlorohexidine diacetate or gluconate,ethanol, and propylene glycol.

Compounds useful as pH regulators include, but are not limited to,glycerol buffers, citrate buffers, borate buffers, phosphate buffers, orcitric acid-phosphate buffers may also be included so as to ensure thatthe pH of the hydrogel composition is compatible with that of anindividual's body surface.

Suitable softeners include citric acid esters, such as triethylcitrateor acetyl triethylcitrate, tartaric acid esters such as dibutyltartrate,glycerol esters such as glycerol diacetate and glycerol triacetate;phthalic acid esters, such as dibutyl phthalate and diethyl phthalate;and/or hydrophilic surfactants, preferably hydrophilic non-ionicsurfactants, such as, for example, partial fatty acid esters of sugars,polyethylene glycol fatty acid esters, polyethylene glycol fatty alcoholethers, and polyethylene glycol sorbitan-fatty acid esters.

Preferred thickeners herein are naturally occurring compounds orderivatives thereof, and include, by way of example: collagen;galactomannans; starches; starch derivatives and hydrolysates; cellulosederivatives such as methyl cellulose, hydroxypropylcellulose,hydroxyethyl cellulose, and hydroxypropyl methyl cellulose; colloidalsilicic acids; and sugars such as lactose, saccharose, fructose andglucose. Synthetic thickeners such as polyvinyl alcohol,vinylpyrrolidone-vinylacetate-copolymers, polyethylene glycols, andpolypropylene glycols may also be used.

In embodiments, the adhesive drug layer is a composition that phaseseparates when moist as described in U.S. Pat. No. 8,481,059, which isincorporated herein by reference.

The adhesive/drug layer comprises one or more drugs, active agents,and/or therapeutic agents. One or more active agents can be included inthe composition of the invention. Suitable active agents that may beincorporated into the adhesives of the invention, include the broadclasses of compounds normally delivered through body surfaces andmembranes such as, by way of illustration and not limitation: analepticagents; analgesic agents; antiarthritic agents; anticancer agents,including antineoplastic drugs; anticholinergics; anticonvulsants;antidepressants; antidiabetic agents; antidiarrheals; antihelminthics;antihistamines; antihyperlipidemic agents; antihypertensive agents;anti-infective agents such as antibiotics, antifungal agents, antiviralagents and bacteriostatic and bactericidal compounds; antiinflammatoryagents; antimigraine preparations; antinauseants; antiparkinsonismdrugs; antipruritics; antipsychotics; antipyretics; antispasmodics;antitubercular agents; antiulcer agents; anxiolytics; appetitesuppressants; attention deficit disorder and attention deficithyperactivity disorder drugs; cardiovascular preparations includingcalcium channel blockers, antianginal agents, central nervous systemagents, beta-blockers and antiarrhythmic agents; caustic agents; centralnervous system stimulants; cough and cold preparations, includingdecongestants; cytokines; diuretics; genetic materials; herbal remedies;hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents;keratolytic agents; leukotriene inhibitors; mitotic inhibitors; musclerelaxants; narcotic antagonists; nicotine; nutritional agents, such asvitamins, essential amino acids and fatty acids; ophthalmic drugs suchas antiglaucoma agents; pain relieving agents such as anesthetic agents;parasympatholytics; peptide drugs; proteolytic enzymes;psychostimulants; respiratory drugs, including antiasthmatic agents;sedatives; steroids, including progestogens, estrogens, corticosteroids,androgens and anabolic agents; smoking cessation agents;sympathomimetics; tissue-healing enhancing agents; tranquilizers;vasodilators including general coronary, peripheral and cerebral;vessicants; and combinations thereof.

In some embodiments, the adhesive/drug layer comprises one or moredrugs, active agents, and/or therapeutic agents for the treatment ofAlzheimer's disease, dementia, and schizophrenia. In some embodiments,adhesive/drug layer comprises one or more drugs including, but notlimited to donepezil and/or memantine.

The adhesive/drug layer may further comprise one or more permeationenhancers. With some active agents, it may be desirable to administerthe agent along with a suitable permeation enhancer in order to achievea therapeutically effective flux through the skin or mucosa. Selectionof suitable permeation enhancers will depend upon the agent beingdelivered, as well as the enhancer's compatibility with the othercomponents of the adhesive. Exemplary permeation enhancers include, byway of illustration and not limitation, sulfoxides such asdimethylsulfoxide and decylmethylsulfoxide; ethers such as diethyleneglycol monoethyl ether and diethylene glycol monomethyl ether;surfactants such as sodium laurate, sodium lauryl sulfate,cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231,182, 184), Tween (20, 40, 60, 80) and lecithin; the 1-substitutedazacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one;alcohols such as ethanol, propanol, octanol, decanol, benzyl alcohol,and the like; fatty acids such as lauric acid, oleic acid and valericacid; fatty acid esters such as isopropyl myristate, isopropylpalmitate, methylpropionate, and ethyl oleate; polyols and estersthereof such as propylene glycol, ethylene glycol, glycerol, butanediol,polyethylene glycol, and polyethylene glycol monolaurate; amides andother nitrogenous compounds such as urea, dimethylacetamide,dimethylformamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine,diethanolamine and triethanolamine; terpenes; alkanones; and organicacids, particularly salicylic acid and salicylates, citric acid andsuccinic acid; and mixtures thereof.

The release of active agents “loaded” into the adhesive of the inventiontypically involves both absorption of water and desorption of the agentvia a swelling-controlled diffusion mechanism. Active agent-containingadhesives may be included in adhesive cushions, wound dressings,transdermal drug delivery devices and the like.

In embodiments, the transdermal delivery system includes an optionalrelease liner 16 that at least partially contacts the adhesive layer.The release liner is a removable covering that prevents loss of theactive agent from the adhesive layer during storage and/or protects thedevice against contamination. The release liner is typically adisposable layer that is removed prior to application of the device tothe treatment site. In some embodiments, the release liner preferablydoes not absorb components of the adhesive layer, including the activeagent. In some embodiments, the release liner preferably impermeable tocomponents of the adhesive layer (including the active agent) andprevents release of components of the adhesive layer through the releaseliner. By impermeable, it is meant that the release liner prevents allor substantially all of the components of the adhesive layer frompassing completely through the release liner. In some embodiments, therelease liner is easily removed or stripped from the adhesive/drug layerwithout removing a portion or a substantial portion of the adhesive druglayer. In some embodiments, the release liner is formed of one or moreof a film, non-woven fabric, woven fabric, laminate, and combinationsthereof. In some embodiments, the release liner is a silicone-coatedpolymer film or paper. In some non-limiting embodiments, the releaseliner is a silicone-coated polyethylene terephthalate (PET) film, apolyester film, a silicone-coated polyester film, a fluorocarbon film,or a fluorocarbon or fluorosilicone coated polymer film. In someembodiments, the material for the release liner is treated with one ormore of silicone, fluorocarbons or fluorosilicones. In one embodiment,the release liner is comprised of fluorocarbon or fluorosilicone coatedPET film. In other embodiments, the release liner is comprised of apolyester foil or other metalized laminate. In some embodiments, therelease liner may include features to increase ease of removal. In someembodiment, the release liner includes a slit or cut 48 as shown in FIG.6 to assist in removal of the liner from the device.

The activity of a transdermal delivery system is defined (and dependentupon) the release rate of the active agent from the system, the totalduration of release from the system, and the surface area of thedelivery system.

Methods of Treatment

Based on the exemplary compositions and devices described herein, andthe data showing release effective long term administration of thedevice, a method for prolonged or long term administration of an activeagent is provided herein.

The methods and systems described herein may be used for treating orpreventing any condition receptive to treatment with a therapeuticagent, drug or active agent as described herein. The methods and systemsdescribed herein are particularly useful for long term transdermaladministration of the therapeutic agent, drug or active agent. Inembodiments, the transdermal device is suitable for administration ofthe active agent or agents for at least about 3-14 days or more.

EXAMPLES

The following examples are illustrative in nature and are in no wayintended to be limiting.

While a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize certain modifications,permutations, additions and sub-combinations thereof. It is thereforeintended that the following appended claims and claims hereafterintroduced are interpreted to include all such modifications,permutations, additions and sub-combinations as are within their truespirit and scope.

All patents, patent applications, patent publications, and otherpublications mentioned herein are hereby incorporated by reference intheir entirety. Where a patent, application, or publication containsexpress definitions, those definitions should be understood to apply tothe incorporated patent, application or publication in which they arefound and not to the present application unless otherwise indicated.

Example 1 Manufacture of Transdermal Delivery System with CompositeBacking

A thin layer of a stretchable or flexible polymer (1-40 mil) islaminated onto an occlusive backing (e.g. Scotchpack™ 1012, polyesterfilm laminate) with an adhesive such as polyisobutylene (PIB), acrylate,a silicone adhesive or other binding agent to form a laminate consistingof occlusive backing/adhesive/stretchable or flexible polymer.

An adhesive drug formulation is blended, coated on a release liner, anddried. The adhesive drug formulation is laminated on the stretchable orflexible polymer side of the backing laminate.

Example 2 Manufacture of Backing Laminate

A thin polyurethane film (0.5 to 1.0 mil) with a paper carrier (e.g. 3MCOTran™ 9701 Backing, 2 mil polyurethane film) is used as the top layer.An occlusive backing, (e.g. Scotchpack™ 1012, polyester film laminate)is laminated on the polyurethane film with an adhesive such aspolyisobutylene (PIB), acrylate, a silicone adhesive or other bindingagent to make a quad laminate consisting of a papercarrier/polyurethane/adhesive/occlusive backing.

The occlusive backing layer is kiss-cut to divide it into multiple,discrete pieces as attached on the flexible elastic layer such as apolyurethane film.

The size of each discrete occlusive backing piece ranges from about 10cm² to about 40 cm² depending on requirements. Each of the discretebacking pieces are adhered or stuck together on the polyurethane film bythe adhesive. The laminate may be rolled in further converting process.

Example 3 Manufacture of Transdermal Delivery System

An adhesive drug formulation is blended, coated on a release liner, anddried. The adhesive drug formulation is laminated on a discretely,kiss-cut occlusive film side of the backing laminate as prepared inExample 2. The paper carrier is removed from the polyurethane side toleave the final formulation laminate. It is die-cut into a required sizewhich is a large patch containing multiple discrete pieces of occlusivefilm but all other layers are continuous. An exemplary patch is shown inFIG. 4B.

Example 4 Manufacture of Transdermal Delivery System with CompositeBacking

A thin layer of KOB 053 woven polyester fabric (Karl Otto GmbH & Co.) islaminated onto a Scotchpak™ 1012 (3M®) polyester film laminate withDuro-Tak 87-2052, an acrylate copolymer pressure sensitive adhesive(Henkel Corporation) to form a laminate consisting of wovenfabric/adhesive/polymer film.

An adhesive drug formulation is blended, coated on a release liner, anddried. The adhesive drug formulation is laminated on the polymer filmside of the backing laminate.

EMBODIMENTS

1. A composite backing layer for use in a transdermal patch, comprising:

a first layer comprised of a polymer fabric or a polymer film having astretchability of at least about 5% in at least one direction;

a second layer comprised of one or more adhesive polymers; and

a third layer comprised of one or more polymers;

wherein the first and second layers are in contact and the second andthird layers are in contact.

2. The composite backing layer of embodiment 1, wherein the polymerfabric or polymer film is comprised of one or more polymers selectedfrom polyesters, polyethylenes, polypropylenes, polyvinylchloride,polyethylene vinyl acetate or copolymers thereof, and polyurethanes.3. The composite backing layer of the combined or separate embodiments1-2, wherein the first layer is selected from a woven polymer fabric, anon-woven polymer fabric, a polymer laminate, and a polymer/metallaminate.4. The composite backing layer of the combined or separate embodiments1-3, wherein the first layer has a thickness of about 0.5-10 mil.5. The composite backing layer of the combined or separate embodiments1-4, wherein one or more of the polymers of the second layer polymershas at least one of (i) a tensile strength of less than about 10 MPa and(ii) an elongation of at least about 50%.6. The composite backing layer of the combined or separate embodiments1-5, wherein the one or more polymers of the second layer are selectedfrom acrylates, acrylate copolymers, polyisobutylene, silicone,polystyrene butyl rubber, polyethylene vinyl acetate and copolymersthereof, and plasticized polymers.7. The composite backing of the combined or separate embodiments 1-6,wherein one or more of the adhesive polymers of the second layer have ashear strength that is less or equal to about 1-25% of the tensilestrength for the polymer.8. The composite backing layer of the combined or separate embodiments1-7, wherein the second layer has a thickness of about 0.5-30 mil.9. The composite backing layer of the combined or separate embodiments1-8, wherein the third layer has a thickness of about 1-40 mil.10. The composite backing layer of the combined or separate embodiments1-9, wherein the third layer is attached to an adhesive drug layercomprising one or more drugs.11. The composite backing layer of the combined or separate embodiments1-10, wherein the first layer, second layer, and third layer arelaminated.12. The composite backing layer of the combined or separate embodiments1-11, wherein at least one of the first layer or the third layer is atleast partially cut.13. A transdermal patch for delivery of an active agent, comprising:(a) a composite backing layer comprising:

a first layer comprised of a polymer fabric or a polymer film having astretchability of at least about 5% in at least one direction;

a second layer comprised one or more adhesive polymers; and

a third layer comprised of one or more polymers;

wherein the first layer, second layer, and third layers are arranged incontact as a composite;

(b) an adhesive drug layer comprising the active agent; and

(c) a release liner.

14. The transdermal patch of embodiment 13, wherein the first layerpolymer fabric or polymer film is comprised of one or more polymersselected from polyesters, polyethylenes, polypropylenes,polyvinylchloride, polyethylene vinyl acetate or copolymers thereof, andpolyurethanes.15. The transdermal patch of the combined or separate embodiments 13-14,wherein the first layer is selected from an occlusive polymer film, apolymer laminate, a polymer/metal laminate, a breathable polymer film, awoven polymer fabric and a non-woven polymer fabric.16. The transdermal patch of the combined or separate embodiments 13-15,wherein the first layer has a thickness of about 0.5-10 mil.17. The transdermal patch of the combined or separate embodiments 13-16,wherein the one or more polymers of the second layer are selected fromacrylates, acrylate copolymers, polyisobutylene, silicone, polystyrenebutyl rubber, polyethylene vinyl acetate and copolymers thereof, andplasticized polymers.18. The transdermal patch of the combined or separate embodiments 13-17,wherein one or more of the adhesive polymers of the second layer have ashear strength that is less or equal to about 1-25% of the tensilestrength for the polymer.19. The transdermal patch of the combined or separate embodiments 13-18,wherein the second layer has a thickness of about 0.5-30 mil.20. The transdermal patch of the combined or separate embodiments 13-19,wherein the third layer has a thickness of about 1-40 mil.21. The transdermal patch of the combined or separate embodiments 13-20,wherein the release liner is formed of a material selected from asilicone coated polyethylene terephthalate, a fluorocarbon, afluorocarbon coated polyethylene terephthalate, and a fluorosiliconecoated polyethylene terephthalate.22. A method of transdermally administering an active agent, comprising:removing a release liner from the transdermal patch or a patchcomprising a backing of the combined or separate embodiments 1-21; andadhering the transdermal patch to the skin of a patient for a period upto about 10 days to deliver the active agent to said patient.23. Acomposite backing layer for use in a transdermal patch, comprising:

a first layer comprised of a polymer fabric or a polymer film;

a second layer comprised of one or more polymers having at least one of(i) a tensile strength of less than about 10 MPa and (ii) an elongationof at least about 50%;

a third layer comprised of one or more stretchable polymers having astretchability of at least about 10%;

wherein the first and second layers are in contact and the second andthird layers are in contact.

24. The composite backing layer of embodiment 23, wherein the polymerfabric or polymer film is comprised of one or more polymers selectedfrom polyesters, polyethylenes, polypropylenes, polyvinylchloride,polyethylene vinyl acetate or copolymers thereof, and polyurethanes.25. The composite backing layer of the combined or separate embodiments23-24, wherein the first layer is selected from a woven, a non-wovenpolymer fabric, an occlusive polymer film, a polymer laminate, and apolymer/metal laminate.26. The composite backing layer of the combined or separate embodiments23-25, wherein the first layer has a thickness of about 0.5-10 mil.27. The composite backing layer of the combined or separate embodiments23-26, wherein the second layer is an adhesive layer.28. The composite backing layer of embodiment 27, wherein adhesive layeris an adhesive tie layer.29. The composite backing layer of the combined or separate embodiments23-28, wherein the one or more polymers of the second layer are selectedfrom acrylates, polyisobutylene, silicone, polystyrene butyl rubber,polyethylene vinyl acetate and copolymers thereof, and plasticizedpolymers.30. The composite backing of the combined or separate embodiments 23-29,wherein the one or more polymers of the second layer have a low shearstrength.31. The composite backing layer of the combined or separate embodiments23-30, wherein the second layer has a thickness of about 0.5-30 mil.32. The composite backing layer of the combined or separate embodiments23-31, wherein the third layer is a non-woven or woven fabric formed ofone or more polymer fibers.33. The composite backing layer of embodiment 32, wherein the one ormore polymer fibers are formed of a polymer fiber selected frompolyester, cotton, silk, polypropylene, nylon, polystyrene,polyvinylchloride, and polyurethanes.34. The composite backing layer of the combined or separate embodiments23-33, wherein the stretchable polymers have a stretchability of atleast about 10% in at least one direction.35. The composite backing layer of the combined or separate embodiments23-34, wherein the third layer has a thickness of about 1-40 mil.36. The composite backing layer of the combined or separate embodiments23-35, wherein the third layer is attached to an adhesive drug layercomprising one or more drugs.37. The composite backing layer of embodiment 36, wherein the backinglayer is impermeable to the one or more drugs.38. The composite backing layer of the combined or separate embodiments23-37, wherein the backing layer is occlusive.39. The composite backing layer of the combined or separate embodiments23-38, wherein the first layer, second layer, and third layer arelaminated.40. The composite backing layer of the combined or separate embodiments23-39, wherein the backing has a surface area of at least about 5-45cm².41 A transdermal patch for delivery of an active agent, comprising:

(a) a composite backing layer comprising:

a first layer comprised of a polymer fabric or a polymer film;

a second layer comprised of one or more polymers having at least one of(i) a tensile strength of less than about 10 MPa and (ii) an elongationof at least about 50%;

a third layer comprised of a material selected from one or morestretchable polymers having a stretchability of at least about 10%, awoven fabric and a non-woven fabric;

wherein the first layer, second layer, and third layers are arranged incontact as a composite;

(b) an adhesive drug layer comprising the active agent; and

(c) a release liner.

42. The transdermal patch of embodiment 41, wherein the first layerpolymer fabric or polymer film is comprised of one or more polymersselected from polyesters, polyethylenes, polypropylenes,polyvinylchloride, polyethylene vinyl acetate or copolymers thereof, andpolyurethanes.43. The transdermal patch of embodiment 41, wherein the first layer isselected from an occlusive polymer film, a polymer laminate, apolymer/metal laminate, a breathable polymer film, a woven polymerfabric and a non-woven polymer fabric.44. The transdermal patch of the combined or separate embodiments 41-43,wherein the first layer has a thickness of about 0.5-10 mil.45. The transdermal patch of the combined or separate embodiments 41-44,wherein the second layer is an adhesive layer.46. The transdermal patch of embodiment 45, wherein the adhesive layeris an adhesive tie layer.47. The transdermal patch of the combined or separate embodiments 41-46,wherein the one or more polymers of the second layer are selected fromacrylates, polyisobutylene, silicone, polystyrene butyl rubber,polyethylene vinyl acetate and copolymers thereof, and plasticizedpolymers.48. The transdermal patch of the combined or separate embodiments 41-47,wherein the one or more polymers of the second layer have a low shearstrength.49. The transdermal patch of the combined or separate embodiments 41-48,wherein the second layer has a thickness of about 0.5-30 mil.50. The transdermal patch of the combined or separate embodiments 41-49,wherein the third layer is a non-woven or woven fabric formed of one ormore polymer fibers.51. The transdermal patch of embodiment 50, wherein the one or morepolymer fibers are formed of a polymer fiber selected from polyester,cotton, silk, polypropylene, nylon, polystyrene, polyvinylchloride, andpolyurethanes.52. The transdermal patch of the combined or separate embodiments 41-51,wherein the stretchable polymers have a stretchability of at least about10% in at least one direction.53. The transdermal patch of the combined or separate embodiments 41-52,wherein the third layer has a thickness of about 1-40 mil.54. The transdermal patch of the combined or separate embodiments 41-53,wherein the backing layer is occlusive.55. The transdermal patch of the combined or separate embodiments 41-54,wherein the backing layer is impermeable to the active agent.56. The transdermal patch of the combined or separate embodiments 41-55,wherein the adhesive drug layer is comprised of an adhesive matrix.57. The transdermal patch of the combined or separate embodiments 41-56,wherein the release liner is a silicone coated material.58. The transdermal patch of embodiment 57, wherein the release liner isa silicone coated PET, fluorocarbon, or fluorocarbon coated PET.59. The transdermal patch of the combined or separate embodiments 41-58,wherein the patch has a surface area of at least about 5-45 cm².60. A transdermal patch for delivery of an active agent, comprising:

(a) a backing layer;

(b) an adhesive drug layer comprising the active agent;

(c) a stretchable layer having a stretchability of at least about 10%,wherein the stretchable layer is embedded within the adhesive druglayer; and

(d) a release liner.

61. The patch of embodiment 60, wherein the stretchable layer iscomprised of at least one polymer having a stretchability of at leastabout 10%, a woven polymer fiber fabric, and a non-woven polymer fiberfabric.

62. A composite backing layer for use in a transdermal patch,comprising:

a first elastic or flexible layer comprised of one or more polymershaving at least one of (i) a tensile strength of less than about 10 MPaor (ii) an elongation of at least about 50%;

a second adhesive layer; and

a third layer comprised of a plurality of separated pieces of anocclusive or substantially occlusive material.

63. The composite backing of embodiment 62, wherein the first layer isformed of a woven or non-woven polymer fabric or an elastic polymerfilm.

64. The composite backing of the combined or separate embodiments 62-63,wherein the elastic polymer film is selected from a polyurethane film, athermoplastic polyester elastomer film, and a polyethylene vinyl acetatefilm.

65. The composite backing of the combined or separate embodiments 62-64,wherein the first layer has a thickness of about 0.5-5 mil.

66. The composite backing of the combined or separate embodiments 62-65,wherein the second adhesive layer is comprised of one or more adhesives.

67. The composite backing of embodiment 66, wherein the adhesive isselected from an acrylic adhesive, a polyisobutylene adhesive, and asilicone adhesive.

68. The composite backing of the combined or separate embodiments 62-67,wherein the second adhesive layer has a thickness of about 0.5-2 mil.

69. The composite backing of the combined or separate embodiments 62-68,wherein the occlusive or substantially occlusive material is selectedfrom polyesters, polyethylenes, a polyethylene vinylacetate,polypropylenes, polystyrenes, polyvinylchloride or copolymers thereof,and nylon.70. The composite backing of embodiment 69, wherein the third layer is alaminate.71. The composite backing of the combined or separate embodiments 62-70,wherein the separated pieces are square or rectangular.72. The composite backing of the combined or separate embodiments 62-71,wherein the third layer has a thickness of about 1-5 mil.73. A method of transdermally administering an active agent, comprising:

removing a release liner from the transdermal patch or a patchcomprising a backing of the combined or separate embodiments 1-72; and

adhering the transdermal patch to the skin of a patient for a period upto about 10 days to deliver the active agent to said patient.

While a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize certain modifications,permutations, additions and sub-combinations thereof. It is thereforeintended that the following appended claims and claims hereafterintroduced are interpreted to include all such modifications,permutations, additions and sub-combinations as are within their truespirit and scope.

All patents, patent applications, patent publications, and otherpublications mentioned herein are hereby incorporated by reference intheir entirety. Where a patent, application, or publication containsexpress definitions, those definitions should be understood to apply tothe incorporated patent, application or publication in which they arefound and not to the present application unless otherwise indicated.

It is claimed:
 1. A transdermal patch, comprising: a composite backinglayer comprised of (i) a first layer comprised of a polymer fabric or apolymer film having a stretchability of at least 5% in at least onedirection; (ii) a second layer comprised of one or more adhesivepolymers; and (iii) a third layer comprised of one or more polymerfilms; wherein the first and second layers are in contact and the secondand third layers are in contact, and wherein the third layer comprisescuts formed at least partially through the layer; and an adhesive matrixdrug layer comprising one or more drugs laminated to the third layer. 2.The transdermal patch of claim 1, wherein the polymer fabric or polymerfilm of the first layer is comprised of one or more polymers selectedfrom polyesters, polyethylenes, polypropylenes, polyvinylchloride,polyethylene vinyl acetate or copolymers thereof, and polyurethanes. 3.The transdermal patch of claim 1, wherein the first layer is selectedfrom a woven polymer fabric, a non-woven polymer fabric, a polymerlaminate, and a polymer/metal laminate.
 4. The transdermal patch ofclaim 1, wherein the first layer has a thickness of about 0.5-10 mil. 5.The transdermal patch of claim 1, wherein one or more of the polymers ofthe second layer has at least one of (i) a tensile strength of less than10 MPa and (ii) an elongation of at least 50%.
 6. The transdermal patchof claim 1, wherein the one or more adhesive polymers of the secondlayer are selected from acrylates, acrylate copolymers, polyisobutylene,silicone, polystyrene butyl rubber, polyethylene vinyl acetate andcopolymers thereof, and plasticized polymers.
 7. The transdermal patchof claim 1, wherein one or more of the adhesive polymers of the secondlayer have a shear strength that is less or equal to about 1-25% of thetensile strength for the polymer.
 8. The transdermal patch of claim 1,wherein the second layer has a thickness of about 0.5-30 mil.
 9. Thetransdermal patch of claim 1, wherein the third layer has a thickness ofabout 1-40 mil.
 10. The transdermal patch of claim 1, wherein the firstlayer, second layer, and third layer are laminated.
 11. The transdermalpatch of claim 1, wherein the third layer is a laminate of two polymerfilms.
 12. The transdermal patch of claim 1, wherein the third layer isflexible laminate of two polymer films.
 13. A transdermal patch fordelivery of an active agent, comprising: (a) a composite backing layercomprising: a first layer comprised of a polymer fabric or a polymerfilm having a stretchability of at least 5% in at least one direction; asecond layer comprised one or more adhesive polymers; and a third layercomprised of one or more polymer films, wherein the third layercomprises cuts formed at least partially through the layer; wherein thefirst layer, second layer, and third layers are arranged in contact as acomposite; (b) an adhesive drug layer comprising the active agent thatis laminated to the third layer; and (c) a release liner.
 14. Thetransdermal patch of claim 13, wherein the first layer polymer fabric orpolymer film is comprised of one or more polymers selected frompolyesters, polyethylenes, polypropylenes, polyvinylchloride,polyethylene vinyl acetate or copolymers thereof, and polyurethanes. 15.The transdermal patch of claim 13, wherein the first layer is selectedfrom an occlusive polymer film, a polymer laminate, a polymer/metallaminate, a breathable polymer film, a woven polymer fabric and anon-woven polymer fabric.
 16. The transdermal patch of claim 13, whereinthe first layer has a thickness of about 0.5-10 mil.
 17. The transdermalpatch of claim 13, wherein the one or more polymers of the second layerare selected from acrylates, acrylate copolymers, polyisobutylene,silicone, polystyrene butyl rubber, polyethylene vinyl acetate andcopolymers thereof, and plasticized polymers.
 18. The transdermal patchof claim 13, wherein one or more of the adhesive polymers of the secondlayer have a shear strength that is less or equal to about 1-25% of thetensile strength for the polymer.
 19. The transdermal patch of claim 13,wherein the second layer has a thickness of about 0.5-30 mil.
 20. Thetransdermal patch of claim 13, wherein the third layer has a thicknessof about 1-40 mil.
 21. The transdermal patch of claim 13, wherein therelease liner is formed of a material selected from a silicone coatedpolyethylene terephthalate, a fluorocarbon, a fluorocarbon coatedpolyethylene terephthalate, and a fluorosilicone coated polyethyleneterephthalate.
 22. The transdermal patch of claim 13, wherein the thirdlayer is flexible laminate of two polymer films.
 23. A method oftransdermally administering an active agent, comprising: removing arelease liner from the transdermal patch comprising: (a) a compositebacking layer comprising: a first layer comprised of a polymer fabric ora polymer film having a stretchability of at least 5% in at least onedirection; a second layer comprised one or more adhesive polymers; and athird layer comprised of one or more polymer films, wherein the thirdlayer comprises cuts formed at least partially through the layer;wherein the first layer, second layer, and third layers are arranged incontact as a composite; (b) an adhesive matrix drug layer comprising theactive agent, the adhesive matrix drug layer laminated to the thirdlayer; and (c) a release liner; and adhering the transdermal patch tothe skin of a patient for a period up to 10 days to deliver the activeagent to said patient.
 24. The method of claim 23, wherein the thirdlayer is a laminate of two polymer films.